The present invention relates to the field of chemistry, and more particularly to a novel and improved process of preparing 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone (also known under the generic name cilostazol), and to highly pure cilostazol.
6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone (also known and referred to herein as Cilostazol), is known as an inhibitor of cell platelet aggregation. Cilostazol is presently marketed (under the brand name Pletal™ by Otsuka American Pharmaceutical, Inc. of Rockville, Md.) as a drug for the treatment of stable intermittent claudication.

Intermittent claudication is a condition caused by narrowing of the arteries that supply the legs with blood. Patients with intermittent claudication suffer from oxygen deficiency in the blood vessels that reach the active leg muscles and thus develop a severe pain, aching or cramping in the legs during walk. This medical condition is typically caused by a peripheral atherosclerotic vascular disease; a condition more commonly known as atherosclerosis or hardening of the arteries. Atherosclerosis occurs when deposits of fatty substances build up, in this case in the legs, leading to an inadequate blood supply to the leg muscles. Intermittent claudication affects tens of million of, predominantly, elderly people. It can greatly impair their ability to walk without considerable discomfort and can seriously affect their ability to exercise or even engage in ordinary activities of daily life.
The presently standard effective treatments of intermittent claudication include intensive exercise regimens, drug treatments, such as pentoxifylline (Trental™) and Cilostazol, and under certain circumstances, re-vascularization surgical procedures (operations to open the leg arteries or provide a replacement artery).
Administration of cilostazol to subjects suffering from intermittent claudication dilates the arteries and thereby improves blood and oxygen supply to the legs, enabling faster and prolonged leg motion. Patients treated with cilostazol reported substantial improvement in both walking distance and walking speed during daily routines.
The mechanism of action of cilostazol is yet unclear. Cilostazol is known as an inhibitor of phosphodiesterase III (PDE III), and as a result exerts vasodilation and inhibition of platelet aggregation activities. Nevertheless, it is not clear whether its beneficial effect on intermittent claudication is attributed to these activities
Cilostazol is now being studied for its use as a therapeutic agent for various indications other than intermittent claudication, such as sexual dysfunctions and additional medical conditions related to blood circulation (see, for example, U.S. Pat. No. 6,187,790).
The synthesis of cilostazol was first described in U.S. Pat. No. 4,277,479 (to Otsuka Pharmaceutical Co.). According to the teachings of this patent, cilostazol and analogs thereof are prepared by a process that involves alkylation of a hydroxycarbostyril derivative, having the general Formula I below, with a tetrazole derivative, having the general Formula II below, wherein X represents a halogen atom and n represents the length of the hydrocarbon chain connecting the tetrazole and the halogen atom (see, Scheme 1 below).

According to the teachings of U.S. Pat. No. 4,277,479, the above reaction is performed at conventional alkaline conditions, using a wide variety of organic and inorganic bases, and in the absence or presence of an inert solvent.
Thus, further according to the teachings of U.S. Pat. No. 4,277,479, cilostazol is prepared from 6-hydroxy-3,4-dihydroquinolinone (also referred to herein throughout as Compound I) and a molar excess of 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole (also referred to herein throughout as Compound II) using 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) as a base and ethanol as a solvent.

Later on, Nishi, et al. (Chem. Pharm. Bull., 31, 1983, 1151-57), described a method of preparing Cilostazol in a higher yield of 74%, by reacting Compound I with a molar excess of Compound II in isopropanol in the presence of potassium hydroxide as a base, and purifying the resulting product by column. chromatography and recrystallization from methanol.
Additional processes for preparing cilostazol are taught in U.S. Pat. No. 6,515,128 and its continuation-in-part U.S. Pat. No. 6,825,214 (to Teva Pharmaceutical Industries Ltd.).
One of these processes involves a phase transfer reaction of Compound I with Compound II in a mixture of a water-immiscible solvent and water in the presence of a water-soluble base, and a quaternary ammonium phase transfer catalyst. The most preferred quaternary ammonium phase transfer catalyst, according to the teachings of these patents, is tricaprylylmethylammonium chloride (Aliquate®336). This process further involves isolation of crude cilostazol from the biphasic mixture and its purification by recrystallization.
The second process involves a reaction of Compound I with a molar excess of Compound II in a non-aqueous hydroxylic solvent, such as 1-butanol, 2-propanol, 2-butanol and amyl alcohol, in the presence of an alkali metal hydroxide, such as potassium hydroxide, and an alkali metal carbonate, such as potassium carbonate. This process further involves isolation of crude cilostazol from the reaction. mixture and its purification by recrystallization.
The third process involves a reaction of Compound I with Compound II in a non-aqueous hydroxylic solvent in the presence of a mixture of an alkali metal hydroxide and an alkali metal carbonate as base, and molecular sieves as an agent of dehydration. This process further involves isolation of crude cilostazol from the reaction mixture and its purification by recrystallization.
The inventors of the present invention reproduced the abovementioned, processes (see, Reference Examples 1-7 in the Examples section hereinbelow), and used HPLC measurements to analyze the composition of the reaction mixture after each step, and to thereby meticulously follow and detect any trace amount of an impurity. The inventors of the present invention have thus uncovered that a substantial amount of the impurity 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-1-[4-(1-cyclohexyl-1H-tetrazol-5yl)-butyl]-3,4-dihydro-1H-quinolin-2-one (also referred to herein throughout as Compound III, presented hereinbelow) is present in the final product (both the crude and purified cilostazol) obtained by all of these processes (see, for example, FIGS. 1-3). The presence of such an impurity was not reported in any of the abovementioned prior art processes. The present inventors have further found that the most substantial amounts of this impurity are obtained in processes which involve inorganic bases (see, for example, Reference Examples 2, 4, 6 and 7 hereinbelow and FIGS. 1-3).

The formation of Compound III as a substantial impurity obtained along with the desired product cilostazol is highly undesirable and pauses a major limitation to the entire synthesis process, particularly due to the findings that such an impurity is exceptionally difficult to remove from the final product by methods suitable for commercial scale (such as recrystallization) and hence may require the use of column chromatography.
Thus, while the prior art teaches several processes for preparing cilostazol, all of these processes are limited in that they require the use of excessive amounts of at least one of the starting materials in order to achieve acceptable reaction yields, and/or the use of reagents which are hazardous, expensive and/or difficult to isolate and remove from the reaction product and/or involve the formation of substantial amounts of Compound III.
As is mentioned above, some of the processes described hereinabove for preparing cilostazol use an excessive amount of at least one of the starting materials. The starting materials typically used in the synthesis of cilostazol, namely, 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole and 6-hydroxy-3,4-dihydroquinolin-2(1H)-one, are expensive compounds. In general, the need to use of molar excess of any of the starting materials, and/or of any expensive reagent, typically indicates that the reaction conditions are less than optimal in terms of yields, impurities and the treatment of waste. Therefore an improved process that would allow an efficient use of the starting materials is critical in the commercial scale production of cilostazol.
In addition, processes which involve the use of organic bases, such as 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), are limited due to the hazardousness of these compounds (DBU, for example, is classified as a harmful substance that may cause burns and lachrymation) and the difficulties encountered while trying to isolate these compounds from the product mixture, which oftentimes lead to use column chromatography or repetitive purification procedures. Similarly, processes in which a phase transfer catalyst, such as the reagent Aliquat®336, is used are limited by the acute hazardousness of this catalyst (Aliquate®336 is classified as a highly toxic substance by inhalation, ingestion or skin absorption, a severe irritant and very destructive of mucous membranes), and the difficulties encountered during purification of the product. Phase transfer catalysts are also oftentimes costly and environmentally unfriendly.
Processes that involve the use of inorganic bases are relatively advantageous in this respect. Inorganic bases are relatively inexpensive, are easy to handle, are relatively environmentally friendly and, most advantageously, can readily be separated from the final product. However, as mentioned above, the present inventors have uncovered that the processes described in the art which use inorganic bases for the synthesis of cilostazol, are severely limited by the substantial formation of Compound III.
There is thus a widely recognized need for, and it would be highly advantageous to have an efficient process for preparing cilostazol devoid of the above limitations.